Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). Recently, the sequence of another heretofore unknown enzyme in the human arachidonic acid/prostaglandin pathway has been reported by T. Hla and K. Nielson, Proc. Natl. Acad. Sci, USA, 89, 7384 (1992) and named "cyclooxygenase II (COX II)" or "prostaglandin G/H synthase II". The discovery of an inducible enzyme associated with inflammation provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects. Cyclooxygenase II is inducible by cytokines or endotoxins and such induction is inhibited by glucocortoids (J. Masferrer, et al, Proc. Natl. Acad. Sci, USA, 89, 3917 (1992)). The 6-methoxy-2-napthylacetic acid metabolite of nabumetone has been found by E. Meade et al to selectively inhibit the COX II enzyme (J. Biol. Chem., 268, 6610 (1993)). In addition, Futaki et al (Prostaglandins, 47, 55 (1994)) have reported that N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide inhibits the COX II enzyme.
The references below that disclose antiinflammatory activity, show continuing efforts to find a safe and effective antiinflammatory agent. The novel thiazoles disclosed herein are such safe and also effective antiinflammatory agents furthering such efforts. The invention compounds are found to show usefulness in vivo as antiinflammatory agents with minimal side effects. The substituted thiazolyl compounds disclosed herein preferably selectively inhibit cyclooxygenase II over cyclooxygenase I.
Diarylheterocycles having antiinflammatory activity are described in copending applications Ser. Nos. 08/160,594 and 08/065,730.
U.S. Pat. No. 5,232,921 to Biziere et al describes 2-alkylaminothiazoles as having an affinity for muscarinic cholinergic receptors.
PCT application WO 93/15071, published Aug. 5, 1993, describes 4-(2-pyridyl)thiazole derivatives as inhibiting gastric acid secretion. Specifically, 2-(phenylmethyl)-4-(2-pyridyl)-5-(2-methylphenyl)thiazole is described. U.S. Pat. No. 4,612,321 to S. Terao and Y. Maki describes 5-pyridylthiazole derivatives, and specifically 5-pyridyl-4-(4-methoxyphenyl)-2-thienylthiazole, as having antiinflammatory activity.
U.S. Pat. No. 4,659,726 to Yoshino et al, describes 4,5-bis(4-methoxyphenyl)-2-(2-pyrrolyl)thiazoles as being effective as platelet aggregation inhibitors. U.S. Pat. No. 5,217,971 to Takasugi et al describes 4,5-diphenylthiazole compounds as having antiinflammatory properties, and specifically 4,5-bis(4-methoxyphenyl)-2-(4-pyridyl)thiazole.
U.S. Pat. No. 4,168,315 to R. Rynbrandt and E. Nishizawa describes 4,5-diphenylthiazole derivatives as being blood platelet agglutination inhibitors. U.S. Pat. No. 4,322,428 to K. Matsumoto and P. Ho, describe 2-(4-halophenyl)-4,5-bis(4-methoxyphenyl)thiazoles as being antiinflammatory. U.S. Pat. No. 4,451,471 to P. Ferrini and R. Goschke describes 2-thio-4,5,diarylthiazole derivatives as having antiinflammatory activity. 4,5-Bis(4-methoxyphenyl) thiazole is described as a synthetic intermediate. PCT application WO 87/6429, published Nov. 5, 1987, describes thienylthiazole compounds, and specifically 4-(4-chlorophenyl)-2-(5-chloro-2-thienyl)-5-(4-methylphenyl)thiazole, as having insecticidal utility.
U.S. Pat. No. 4,051,250 to Dahm et al describes 4,5-diarylthiazole compounds as being antiinflammatory. Specifically, 2-chloro-4-(4-chlorophenyl)-5-(4-methylmercaptophenyl)thiazole is described as a synthetic intermediate. European Application EP592,664, published Apr. 20, 1994, describes 4,5-diphenylthiazoles as having antiinflammatory activity, and specifically 4-[4-(methylsulfonyloxy)phenyl]-5-phenyl-2-[bis(N-methylsulfonyl)amino]thi azole. Seko et al [Chem. Pharm. Bull., 39, 651 (1991)] describe the platelet aggregation and cyclooxygenase inhibitory activity of 4,5-diphenylthiazoles, and specifically of 4,5-bis(4-methylthiophenyl)-2-(1,5-dimethyl-2-pyrrolyl)thiazole.
U.S. Pat. No. 4,632,930 to D. Carini and R. Wexler describes alkylaryl thiazole derivatives, and specifically 5-phenyl-4-(methylsulfonylphenyl)-.alpha.,.alpha.-bis(trifluoromethyl)thia zole-2-methanol, as having antihypertensive properties.